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January 20, 2011

A tribute to Ernest "Bun" McCulloch (1926-2011)

 

Mccullochb&w On January 20, 2011 Ernest (“Bun”) McCulloch passed away. Although Bun was known to the young generation of stem cell researchers only by reputation, for those of us who knew him “back then” he was an icon. “Back then” was the 60s and 70s when the group led by Bun McCulloch and Jim Till conducted experiments that led to the concept of stem cells as the source of all cell types in the blood-forming system, proved their existence, described their properties and set the stage for the life-saving procedure of bone marrow transplantation.

Back then we didn’t think much about stem cells in other tissues, and it was more than 15 years before stem cells were identified and characterised in other tissues and in the developing embryo.

Back then I was a PhD student under the supervision of Jim Till. I had come from a physics background as had Jim. Dr. McCulloch, as I called him back then, was a haematologist, a visionary, a descriptive scientist who loved to dream about the art of the possible. His knowledge of the blood-forming system was prodigious, but he was not content with its description. He wanted to know how it developed and how it sustained itself. Jim Till, being a quantitative scientist was the driving force behind the idea that to understand the biology required quantitative measurements.

So when nodules of growing cells were seen in the spleens of irradiated mice who had received bone marrow transplants, it was the two of them together who realized that these could be clones of cells derived from multi-potential precursors. We didn’t use the term “stem cells” back then. Together they set out to develop the spleen colony assay as a quantitative assay for stem cell number, to demonstrate the presence of multiple cell types in the colonies through detailed cytology and to prove that the colonies were derived from single cells. It was a very productive time, with many graduate students and post-doctoral fellows contributing to the effort. You will recognize some of the names – Andy Becker, Allen and Gillian Wu, Ron Worton, Paul Austin, Don Sutherland, Norman Iscove, Allan Bernstein, Bob Phillips, Rick Miller, and somewhat later Connie and Allen Eaves.  Many of them went on to train the next generation of stem cell biologists. 

At the beginning I was afraid of Dr. McCulloch, so I stuck to getting advice from Dr. Till. The odd time I did speak to him, I felt that he was thinking so far ahead of me that I struggled to understand. Slowly, after a great many weekly group seminars (held in the office of Lou Siminovitch until we outgrew it) I began to be comfortable speaking briefly to Dr. McCulloch, but still didn’t venture into the inner sanctum of his office. Finally, one day after I had generated my first substantial results I presented them to Jim who suggested that I tell Bun as well. I made an appointment and went to see him. He listened, agreed on the importance of the work and without hesitation began to suggest future experiments – dozens of them – so many I couldn’t keep track. This was my first real encounter with the brilliant mind and quick intellect of Bun McCulloch.

Soon I was making regular visits to his office.The next memorable encounter was when I wrote my first paper on stem cells. Like all graduate students, my first paper was way too long and had unnecessary detail that only I deemed to be important. Jim had told me that, and suggested ways to improve it. Bun had received a copy of the manuscript and invited me to his office. He agreed with Jim about the unnecessary detail, and asked if I would like to know how he would write it. I said yes. So, he picked up his Dictaphone and in the next 20 minutes he paced the floor in his office while he dictated a manuscript from start to finish. In those 20 minutes he transformed my pedantic, thoughtful, careful, and fully detailed manuscript into a lively, punchy and dramatic account demonstrating that stem cells defined by the spleen colony assay are distinct entities from the other known precursor cells of the blood-forming system. I was transfixed. It had never occurred to me that anyone could do that. To be sure, his dictated version needed some editing and polishing, but the essence of what he dictated remained intact. It was a valuable lesson, and it completely changed my concept of how to write a scientific paper, even though I never did learn to dictate them in 20 minutes.  

Even though Bun had been retired for many years, he will be missed by all of us who knew him well and admired his intellect, his dedication and his profound influence on the field of stem cell biology. For Jim Till, I am sure it will be like losing a twin who for many years had been joined at the hip. And for the younger generation of stem cell scientists it will be a time to pause and reflect on those early experiments, carried out long before the term “stem cell” was a household word, and long before the profound importance of stem cells was recognized. Bun and Jim were true pioneers whose work dictated how we think about the human body, its development and its replenishment. Bun can rest knowing that he truly made a difference.  

-- Ron Worton, former Scientific Director of the Stem Cell Network

 

I invite additional memories, thoughts and comments to this blog as a public, scientific memorial of the incredible Bun McCulloch.

 

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BBC Radio aired an obituary for Dr. McCulloch on February 11, 2011. You can listen to it here (starts at approx minute 6) http://www.bbc.co.uk/programmes/b00y9tbz#synopsis

Additional tributes to Dr. McCulloch can be found at the University Health Network in Toronto: http://www.uhn.ca/applications/iNews/ViewStory.aspx?s_id=1214 and on the Canadian Stem Cell Foundation, which will be publishing a book on Till and McCulloch later this year: http://stemcellfoundation.ca/blog/

Although I had heard many stories of Dr. McCulloch and his formidable intellect and influence, it was not until I met him for the first time that I truly understood how far that extended:

Dr. McCulloch had been invited to give a talk, along with his erstwhile colleague, Dr. James Till, at the 2004 meeting of the Stem Cell Network. The meeting itself was attended by close to 400 Canadian scientists as well as the heads of the 15 major health-funding agencies from around the world, including NIH, MRC, CIHR, and many others, who were in Montreal for a special session on the regulation of stem cell research. I should add that at this time Dr. McCulloch had already turned 80, and naturally many of us (who did not know him well), expected to hear him reminisce about his seminal discovery over 40 years prior. Boy, were we wrong! Instead, he held the audience spellbound, as he delivered a 35 minute talk, without slides, where he reviewed all of the recent literature about the concept of cancer stem cells, and articulated why he believed the concept to be relevant, and why it would be the next big area in stem cell research. He received a deserved standing ovation, but remarkably, a little over a year later Dr. Peter Dirks (University of Toronto) validated Dr. McCulloch’s deductive reasoning by publishing a paper identifying stem cells in solid tumours in the brain for the first time. Since that meeting, the Network itself has invested over $ 2 million in its cancer stem cell initiative, from which three clinical trials have now been initiated, and the Cancer Stem Cell Consortium has been established and invested over $80 million in two projects in collaboration with the California Institute of Regenerative Medicine.

The meeting also provided a remarkable insight into McCulloch and Till’s influence. Dr. Alan Bernstein, who was then President of CIHR, went to the podium to thank Dr. McCulloch, and proceeded to conduct an “experiment”, which lives with me to this day. First he asked everyone in the room who had completed their post-doc under Drs. Till and McCulloch to stand up. About half a dozen scientists did, including Dr. Ron Worton, Dr. Connie Eaves, Dr. Norm Iscove, and Dr. Keith Humphries. Dr. Bernstein noted he himself came from their lab. He then invited the post-docs of those scientists to stand up – about another 25-30 or so, including Dr. Guy Sauvageau, Dr. Peter Zandstra, Dr. John Dick and many others. Then he invited the post-docs of those post-docs to stand up. By the time he was finished, over 200 people (easily half the room) were standing, all of who could trace their scientific lineage directly to the labs of Drs. Till and McCulloch. What also struck home that day were the values they had promoted in their progeny. Dr. McCulloch was a haematologist and Dr. Till was a physicist, and though I am told they had many robust scientific exchanges, they realised that it was only through collaboration and in applying different knowledge and disciplines to a problem that they were able to make the scientific progress they did. This attitude, instilled in their post-docs, pervades the Canadian stem cell research community today, and perhaps explains why this country has been able to punch above it weight for so long in this field.

Dr. McCulloch will be sorely missed, but he has a tremendous legacy, not just in an outstanding work of science and papers, but in a cadre of scientific leaders who will continue to shape stem cell research for years to come.

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